Evolution of The Continuum of Care for Metastatic CRC - Episode 7
Transcript:Johanna C. Bendell, MD: About 8% to 10% of patients with metastatic colorectal colon cancer have a BRAF V600E mutation. This actually portends a very poor prognosis. Typically, the survivals are about half that of BRAF wild-type patients. We need to find other treatment options for these patients with BRAF-mutated disease. We’ve tried more intense first-line therapies, which seem promising given data with FOLFOXIRI [fluorouracil/folinic acid/oxaliplatin/irinotecan] plus bevacizumab [Avastin] for these patients. We’ve also used targeted agents, such as in the BEACON study. We’ve also seen NCCN [National Comprehensive Cancer Network] guidelines change to suggest that the combination of vemurafenib [Zelboraf], a BRAF inhibitor, plus cetuximab [Erbitux] and irinotecan is a good second-line regimen for patients with BRAF-mutated disease.
Patients with BRAF-mutated colorectal cancer don’t tend to respond like patients with BRAF-mutated melanoma to BRAF inhibitors. There was really amazing scientific work done that showed that in colon cancer, in particular, when you give a BRAF inhibitor or you inhibit this pathway, you get reflective upregulation of the EGFR [epidermal growth factor receptor] receptor. If we give a combination of an EGFR inhibitor, or an EGFR antibody, plus a BRAF inhibitor—or an EGFR inhibitor plus a BRAF inhibitor plus a MEK inhibitor—to double-hit the pathway, we’ve seen much better efficacy.
Tanios Bekaii-Saab, MD: The BEACON study is a study looking at essentially bringing a new standard to patients who have metastatic colorectal cancer, specifically those with wild-type RAS but BRAF V600E mutations. Those patients do incredibly poorly and their prognosis is terrible. In colon cancer, their median survival is about 10 to 12 months, which is no better than historical 5-FU [fluorouracil] for the general population. For first-line therapy, usually we go with FOLFOXIRI and bevacizumab. When we get to second-line therapy, we don’t have as many options for these patients.
Of course, we can go to regorafenib [Stivarga] or TAS-102, but we rarely salvage patients in that setting. One of the challenges is that these are tumors that are resistant to EGFR inhibitors. They don’t respond to them. They tend to have a poor response across the board to chemotherapy as well.
Initial targeting of the tumor started with BRAF inhibitors, vemurafenib and the like, or encorafenib and others. The problem was that the response rate was less than 5%. In melanoma, to contrast that, in the presence of BRAF V600E mutations, if you use these RAF inhibitors, you have a 70% response rate. The understanding was that there’s something else driving that tumor when you block RAF. When you look upstream, you look at EGFR. EGFR, because of the loop mechanism, becomes relevant again and suddenly takes over. It made a lot of sense actually to block EGFR along with RAF. Here’s a disease that doesn’t respond to EGFR inhibitors. When you block RAF, now you can block EGFR and induce a response when you create a blockade.
Then comes MEK, and MEK is downstream from BRAF. Some goes upstream, some goes downstream, and the triplet essentially blocks every aspect of that pathway. It makes sense to actually add the 3 together. Interestingly, when you actually use each one of them separately, you have more toxicities than when you use all 3. There’s some protective mechanisms in the skin and the bowels that actually prevents some of the toxicities we traditionally see with these agents. It ends up being a little bit safer than expected at least.
The study that was done in this setting, the BEACON trial—which is looking at the triplet versus a doublet versus chemotherapy, plus cetuximab as the control arm—is ongoing. The study actually closed in the United States because in the United States, the NCCN guidelines allow us to use a regimen that includes a RAF inhibitor, which unfortunately made it very difficult to approve this study. It was a little bit of a disservice to the study. In the rest of the world, the study is ongoing.
There was an initial study with about 30 or more patients that looked at 3 drugs, a triplet—encorafenib, binimetinib, and cetuximab—that was presented. It was the safety lead into the BEACON study. It showed a response rate of 40% for the triplet, including 2 to 3 CRs, complete responders, in a disease where you expect zero0. Some of these responses were quite deep and quite significant. That led to the breakthrough application to the FDA, and hopefully we’ll ultimately make this available to our patients. Especially since, again, we’re talking a patient population that has no options whatsoever following first-line treatment failure.
Now, when we looked at the worldwide access to these drugs, it’s unlikely to become available at the same rate that it does in the United States. The BEACON trial will give us the final answer about 2 things. Is the 3-drug regimen going to be superior to standard chemotherapy? If I was a guessing man, I’d say yes. The next question is, do we really need 3 drugs? Can we get away with 2 drugs? For that, we’ll see. That is probably the more interesting question from this study.
In terms of our patients right now, we have a regimen available and we’ll have hopefully another regimen with these 3 drugs, which would be my preferred option for my patients if it becomes available to the clinic. That would be a good salvage regimen for patients with BRAF V600E mutations.
Transcript Edited for Clarity.